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MUTATIONS INDUCED BY URBAN AIR AND DRINKING WATER: DO THEY LEAVE A MUTATIONAL SIGNATURE IN HUMAN TUMORS?
Citation:
DeMarini, D M. MUTATIONS INDUCED BY URBAN AIR AND DRINKING WATER: DO THEY LEAVE A MUTATIONAL SIGNATURE IN HUMAN TUMORS? Presented at Environmental Mutagen Society, Miami Beach, FL, May 10-14, 2003.
Description:
Mutations Induced by Urban Air and Drinking Water: Do They Leave a Mutational Signature in Human Tumors?
Mutation spectra of complex environmental mixtures have been determined thus far only in Salmonella. We have determined mutation spectra for the particulate organics and various fractions of urban air and municipal waste incinerator emissions and compared the results to single compounds representative of the primary chemical classes of mutagens in these mixtures. We have performed similar studies with cigarette smoke condensate and organic extracts of drinking water. In all cases, the mutation spectrum of the mixture reflected the dominance of one or a few chemical classes within the mixture. The mutation spectrum of organic extracts of chlorinated drinking water is similar to that of MX, which is a potent mutagen in drinking water. However, no molecular epidemiology studies have been performed for drinking water. Thus, whether MX or any other mutagens in drinking water leave a mutational signature in human tumors is unknown. The mutation spectra of sunlight and cigarette smoke in Salmonella were similar to those found in the TP53 gene of skin or lung tumors, respectively, in people whose tumors were associated with exposure to these agents. The primary class of base substitution induced by a single agent is generally the same across species, reflecting the conserved nature of DNA replication and repair processes. Consistent with this is our recent finding that the mutation spectrum in the TP53 and KRAS genes of nonsmokers exposed to PAH-rich coal emissions reflects that of PAHs determined in laboratory systems. Complex mixture-induced mutation spectra can be modeled by the predominant mutagenic chemical classes in the mixture and even by a single model compound in that chemical class. Our results support the view that mutation spectra in specific tumor genes reflect, in concert with selection, the primary DNA damage induced by mutagenic exposure linked epidemiologically to those tumors. [Abstract does not necessarily reflect the policy of the US EPA.]